Project Summary Hyperinsulinemic hypoglycemia (HH) is one of the most frequent causes of persistent hypoglycemia in infants and can result in seizures, developmental delays, learning disabilities, and even death. The most severe form of HH is inherited and referred to as congenital hyperinsulinism (CHI). CHI largely results from mutations in key genes in the insulin secretion pathway in the islets of Langerhans in the pancreas. Suspicion of CHI is confirmed by tests including the need to implement a high glucose infusion rate to maintain normal blood glucose levels. Currently, the only medical therapies used to treat CHI are used off-label. Typically, diazoxide (an insulin secretion inhibitor) is tried first, though it is often ineffective and has a side effect that causes abnormal and excessive hair growth over much of the body. The peptide sst receptor agonist octreotide is also used off-label for patients that are unresponsive to diazoxide or in conjunction with poor responders. Its pharmacological profile (sst2>sst5) leads to a host of unwanted side effects, including suppression of glucagon secretion which is detrimental to the CHI patient's utmost need, as well as inhibition of the growth hormone axis at the pituitary. Despite their poor profiles, these therapies are tried because the next line of treatment is typically a partial or full pancreatectomy. Even when successful, the result of this surgery is that the patient becomes diabetic and must actively manage glucose for the rest of their lives. Therefore, a significant unmet medical need exists for agents designed to specifically and effectively treat CHI. Here, we lay out our plan to develop orally-available, selective sst5-, sst3-, and/or dual sst5/3 agonists for the treatment of infants and children with CHI and other hyperinsulinemic disorders. Such a compound represents a major advance for infants with CHI and promises to provide specifically directed insulin control with the goal of preventing or delaying pancreatectomy without the excess of side effects that are carried along with current treatments.